Safety, Tolerability, and Preliminary Effectiveness of CTH120 in Fragile X Syndrome

Summary

The purpose of this Phase IIa study is to evaluate the safety, tolerability, and effectiveness of CTH120 in adult males with Fragile X syndrome.

Timeline

Start

2026-05-21

Primary completion

2027-05

Completion

2027-05

Publications

• Background EMEA, "Committee for Medicinal Products for Human Use (CHMP) Guideline on strategies to identify and mitigate risks for first-in-human and early clinical trials with investigational medicinal products," EMEA/CHMP/SWP/28367/07, 2017, Accessed: Jul. 07, 2022. [Online]. Available: www.ema.europa.eu/contact
• Background Myrick LK, Nakamoto-Kinoshita M, Lindor NM, Kirmani S, Cheng X, Warren ST. Fragile X syndrome due to a missense mutation. Eur J Hum Genet. 2014 Oct;22(10):1185-9. doi: 10.1038/ejhg.2013.311. Epub 2014 Jan 22.
• Background Quartier A, Poquet H, Gilbert-Dussardier B, Rossi M, Casteleyn AS, Portes VD, Feger C, Nourisson E, Kuentz P, Redin C, Thevenon J, Mosca-Boidron AL, Callier P, Muller J, Lesca G, Huet F, Geoffroy V, El Chehadeh S, Jung M, Trojak B, Le Gras S, Lehalle D, Jost B, Maury S, Masurel A, Edery P, Thauvin-Robinet C, Gerard B, Mandel JL, Faivre L, Piton A. Intragenic FMR1 disease-causing variants: a significant mutational mechanism leading to Fragile-X syndrome. Eur J Hum Genet. 2017 Apr;25(4):423-431. doi: 10.1038/ejhg.2016.204. Epub 2017 Feb 8.
• Background Hagerman RJ, Berry-Kravis E, Hazlett HC, Bailey DB Jr, Moine H, Kooy RF, Tassone F, Gantois I, Sonenberg N, Mandel JL, Hagerman PJ. Fragile X syndrome. Nat Rev Dis Primers. 2017 Sep 29;3:17065. doi: 10.1038/nrdp.2017.65.
• Background Wang LW, Berry-Kravis E, Hagerman RJ. Fragile X: leading the way for targeted treatments in autism. Neurotherapeutics. 2010 Jul;7(3):264-74. doi: 10.1016/j.nurt.2010.05.005.
• Background Grigsby J. The fragile X mental retardation 1 gene (FMR1): historical perspective, phenotypes, mechanism, pathology, and epidemiology. Clin Neuropsychol. 2016 Aug;30(6):815-33. doi: 10.1080/13854046.2016.1184652. Epub 2016 Jun 29.
• Background Banerjee A, Ifrim MF, Valdez AN, Raj N, Bassell GJ. Aberrant RNA translation in fragile X syndrome: From FMRP mechanisms to emerging therapeutic strategies. Brain Res. 2018 Aug 15;1693(Pt A):24-36. doi: 10.1016/j.brainres.2018.04.008. Epub 2018 Apr 10.
• Background Bakker CE, Oostra BA. Understanding fragile X syndrome: insights from animal models. Cytogenet Genome Res. 2003;100(1-4):111-23. doi: 10.1159/000072845.
• Background Mientjes EJ, Nieuwenhuizen I, Kirkpatrick L, Zu T, Hoogeveen-Westerveld M, Severijnen L, Rife M, Willemsen R, Nelson DL, Oostra BA. The generation of a conditional Fmr1 knock out mouse model to study Fmrp function in vivo. Neurobiol Dis. 2006 Mar;21(3):549-55. doi: 10.1016/j.nbd.2005.08.019. Epub 2005 Oct 26.
• Background Gaudissard J, Ginger M, Premoli M, Memo M, Frick A, Pietropaolo S. Behavioral abnormalities in the Fmr1-KO2 mouse model of fragile X syndrome: The relevance of early life phases. Autism Res. 2017 Oct;10(10):1584-1596. doi: 10.1002/aur.1814. Epub 2017 Jun 7.
• Background Darnell JC, Klann E. The translation of translational control by FMRP: therapeutic targets for FXS. Nat Neurosci. 2013 Nov;16(11):1530-6. doi: 10.1038/nn.3379. Epub 2013 Apr 14.
• Background Richter JD, Bassell GJ, Klann E. Dysregulation and restoration of translational homeostasis in fragile X syndrome. Nat Rev Neurosci. 2015 Oct;16(10):595-605. doi: 10.1038/nrn4001. Epub 2015 Sep 9.
• Background Gholizadeh S, Halder SK, Hampson DR. Expression of fragile X mental retardation protein in neurons and glia of the developing and adult mouse brain. Brain Res. 2015 Jan 30;1596:22-30. doi: 10.1016/j.brainres.2014.11.023. Epub 2014 Nov 20.
• Background Feng Y, Gutekunst CA, Eberhart DE, Yi H, Warren ST, Hersch SM. Fragile X mental retardation protein: nucleocytoplasmic shuttling and association with somatodendritic ribosomes. J Neurosci. 1997 Mar 1;17(5):1539-47. doi: 10.1523/JNEUROSCI.17-05-01539.1997.
• Background Hanson AC, Hagerman RJ. Serotonin dysregulation in Fragile X Syndrome: implications for treatment. Intractable Rare Dis Res. 2014 Nov;3(4):110-7. doi: 10.5582/irdr.2014.01027.
• Background Boccuto L, Chen CF, Pittman AR, Skinner CD, McCartney HJ, Jones K, Bochner BR, Stevenson RE, Schwartz CE. Decreased tryptophan metabolism in patients with autism spectrum disorders. Mol Autism. 2013 Jun 3;4(1):16. doi: 10.1186/2040-2392-4-16.
• Background Chandana SR, Behen ME, Juhasz C, Muzik O, Rothermel RD, Mangner TJ, Chakraborty PK, Chugani HT, Chugani DC. Significance of abnormalities in developmental trajectory and asymmetry of cortical serotonin synthesis in autism. Int J Dev Neurosci. 2005 Apr-May;23(2-3):171-82. doi: 10.1016/j.ijdevneu.2004.08.002.
• Background Wang H, Wu LJ, Kim SS, Lee FJ, Gong B, Toyoda H, Ren M, Shang YZ, Xu H, Liu F, Zhao MG, Zhuo M. FMRP acts as a key messenger for dopamine modulation in the forebrain. Neuron. 2008 Aug 28;59(4):634-47. doi: 10.1016/j.neuron.2008.06.027.
• Background Gkogkas CG, Khoutorsky A, Cao R, Jafarnejad SM, Prager-Khoutorsky M, Giannakas N, Kaminari A, Fragkouli A, Nader K, Price TJ, Konicek BW, Graff JR, Tzinia AK, Lacaille JC, Sonenberg N. Pharmacogenetic inhibition of eIF4E-dependent Mmp9 mRNA translation reverses fragile X syndrome-like phenotypes. Cell Rep. 2014 Dec 11;9(5):1742-1755. doi: 10.1016/j.celrep.2014.10.064. Epub 2014 Nov 26.
• Background Wahlstrom-Helgren S, Klyachko VA. GABAB receptor-mediated feed-forward circuit dysfunction in the mouse model of fragile X syndrome. J Physiol. 2015 Nov 15;593(22):5009-24. doi: 10.1113/JP271190. Epub 2015 Oct 2.
• Background Kashima R, Roy S, Ascano M, Martinez-Cerdeno V, Ariza-Torres J, Kim S, Louie J, Lu Y, Leyton P, Bloch KD, Kornberg TB, Hagerman PJ, Hagerman R, Lagna G, Hata A. Augmented noncanonical BMP type II receptor signaling mediates the synaptic abnormality of fragile X syndrome. Sci Signal. 2016 Jun 7;9(431):ra58. doi: 10.1126/scisignal.aaf6060.
• Background Sidhu H, Dansie LE, Hickmott PW, Ethell DW, Ethell IM. Genetic removal of matrix metalloproteinase 9 rescues the symptoms of fragile X syndrome in a mouse model. J Neurosci. 2014 Jul 23;34(30):9867-79. doi: 10.1523/JNEUROSCI.1162-14.2014.
• Background Pasciuto E, Ahmed T, Wahle T, Gardoni F, D'Andrea L, Pacini L, Jacquemont S, Tassone F, Balschun D, Dotti CG, Callaerts-Vegh Z, D'Hooge R, Muller UC, Di Luca M, De Strooper B, Bagni C. Dysregulated ADAM10-Mediated Processing of APP during a Critical Time Window Leads to Synaptic Deficits in Fragile X Syndrome. Neuron. 2015 Jul 15;87(2):382-98. doi: 10.1016/j.neuron.2015.06.032.
• Background Danesi C, Achuta VS, Corcoran P, Peteri UK, Turconi G, Matsui N, Albayrak I, Rezov V, Isaksson A, Castren ML. Increased Calcium Influx through L-type Calcium Channels in Human and Mouse Neural Progenitors Lacking Fragile X Mental Retardation Protein. Stem Cell Reports. 2018 Dec 11;11(6):1449-1461. doi: 10.1016/j.stemcr.2018.11.003. Epub 2018 Nov 29.
• Background Pilaz LJ, Lennox AL, Rouanet JP, Silver DL. Dynamic mRNA Transport and Local Translation in Radial Glial Progenitors of the Developing Brain. Curr Biol. 2016 Dec 19;26(24):3383-3392. doi: 10.1016/j.cub.2016.10.040. Epub 2016 Dec 1.
• Background Bailey DB Jr, Raspa M, Olmsted M, Holiday DB. Co-occurring conditions associated with FMR1 gene variations: findings from a national parent survey. Am J Med Genet A. 2008 Aug 15;146A(16):2060-9. doi: 10.1002/ajmg.a.32439.
• Background Irwin SA, Patel B, Idupulapati M, Harris JB, Crisostomo RA, Larsen BP, Kooy F, Willems PJ, Cras P, Kozlowski PB, Swain RA, Weiler IJ, Greenough WT. Abnormal dendritic spine characteristics in the temporal and visual cortices of patients with fragile-X syndrome: a quantitative examination. Am J Med Genet. 2001 Jan 15;98(2):161-7. doi: 10.1002/1096-8628(20010115)98:23.0.co;2-b.
• Background Berry-Kravis E, Raspa M, Loggin-Hester L, Bishop E, Holiday D, Bailey DB. Seizures in fragile X syndrome: characteristics and comorbid diagnoses. Am J Intellect Dev Disabil. 2010 Nov;115(6):461-72. doi: 10.1352/1944-7558-115.6.461.
• Background McLennan Y, Polussa J, Tassone F, Hagerman R. Fragile x syndrome. Curr Genomics. 2011 May;12(3):216-24. doi: 10.2174/138920211795677886.
• Background Sauna-Aho O, Bjelogrlic-Laakso N, Siren A, Arvio M. Signs indicating dementia in Down, Williams and Fragile X syndromes. Mol Genet Genomic Med. 2018 Sep;6(5):855-860. doi: 10.1002/mgg3.430. Epub 2018 Jul 3.
• Background Bartholomay KL, Lee CH, Bruno JL, Lightbody AA, Reiss AL. Closing the Gender Gap in Fragile X Syndrome: Review on Females with FXS and Preliminary Research Findings. Brain Sci. 2019 Jan 12;9(1):11. doi: 10.3390/brainsci9010011.
• Background Cordeiro L, Ballinger E, Hagerman R, Hessl D. Clinical assessment of DSM-IV anxiety disorders in fragile X syndrome: prevalence and characterization. J Neurodev Disord. 2011 Mar;3(1):57-67. doi: 10.1007/s11689-010-9067-y. Epub 2010 Dec 3.
• Background Utari A, Adams E, Berry-Kravis E, Chavez A, Scaggs F, Ngotran L, Boyd A, Hessl D, Gane LW, Tassone F, Tartaglia N, Leehey MA, Hagerman RJ. Aging in fragile X syndrome. J Neurodev Disord. 2010 Jun;2(2):70-76. doi: 10.1007/s11689-010-9047-2. Epub 2010 May 12.
• Background Leehey MA. Fragile X-associated tremor/ataxia syndrome: clinical phenotype, diagnosis, and treatment. J Investig Med. 2009 Dec;57(8):830-6. doi: 10.2310/JIM.0b013e3181af59c4.
• Background Tassone F. Advanced technologies for the molecular diagnosis of fragile X syndrome. Expert Rev Mol Diagn. 2015;15(11):1465-73. doi: 10.1586/14737159.2015.1101348. Epub 2015 Oct 21.
• Background Rajan-Babu IS, Chong SS. Molecular Correlates and Recent Advancements in the Diagnosis and Screening of FMR1-Related Disorders. Genes (Basel). 2016 Oct 14;7(10):87. doi: 10.3390/genes7100087.
• Background Kidd SA, Lachiewicz A, Barbouth D, Blitz RK, Delahunty C, McBrien D, Visootsak J, Berry-Kravis E. Fragile X syndrome: a review of associated medical problems. Pediatrics. 2014 Nov;134(5):995-1005. doi: 10.1542/peds.2013-4301. Epub 2014 Oct 6.
• Background Crawford DC, Acuna JM, Sherman SL. FMR1 and the fragile X syndrome: human genome epidemiology review. Genet Med. 2001 Sep-Oct;3(5):359-71. doi: 10.1097/00125817-200109000-00006.
• Background Tassone F, Iong KP, Tong TH, Lo J, Gane LW, Berry-Kravis E, Nguyen D, Mu LY, Laffin J, Bailey DB, Hagerman RJ. FMR1 CGG allele size and prevalence ascertained through newborn screening in the United States. Genome Med. 2012 Dec 21;4(12):100. doi: 10.1186/gm401. eCollection 2012.
• Background Hunter J, Rivero-Arias O, Angelov A, Kim E, Fotheringham I, Leal J. Epidemiology of fragile X syndrome: a systematic review and meta-analysis. Am J Med Genet A. 2014 Jul;164A(7):1648-58. doi: 10.1002/ajmg.a.36511. Epub 2014 Apr 3.
• Background Coffee B, Keith K, Albizua I, Malone T, Mowrey J, Sherman SL, Warren ST. Incidence of fragile X syndrome by newborn screening for methylated FMR1 DNA. Am J Hum Genet. 2009 Oct;85(4):503-14. doi: 10.1016/j.ajhg.2009.09.007.
• Background Kenny A, Wright D, Stanfield AC. EEG as a translational biomarker and outcome measure in fragile X syndrome. Transl Psychiatry. 2022 Jan 24;12(1):34. doi: 10.1038/s41398-022-01796-2.
• Background Ethridge LE, Pedapati EV, Schmitt LM, Norris JE, Auger E, De Stefano LA, Sweeney JA, Erickson CA. Validating brain activity measures as reliable indicators of individual diagnostic group and genetically mediated sub-group membership Fragile X Syndrome. Sci Rep. 2024 Oct 3;14(1):22982. doi: 10.1038/s41598-024-72935-6.
• Background Klusek J, Moser C, Schmidt J, Abbeduto L, Roberts JE. A novel eye-tracking paradigm for indexing social avoidance-related behavior in fragile X syndrome. Am J Med Genet B Neuropsychiatr Genet. 2020 Jan;183(1):5-16. doi: 10.1002/ajmg.b.32757. Epub 2019 Aug 16.
• Background Farzin F, Scaggs F, Hervey C, Berry-Kravis E, Hessl D. Reliability of eye tracking and pupillometry measures in individuals with fragile X syndrome. J Autism Dev Disord. 2011 Nov;41(11):1515-22. doi: 10.1007/s10803-011-1176-2.
• Background Dueck A, Reis O, Bastian M, van Treeck L, Weirich S, Haessler F, Fiedler A, Koelch M, Berger C. Feasibility of a Complex Setting for Assessing Sleep and Circadian Rhythmicity in a Fragile X Cohort. Front Psychiatry. 2020 May 14;11:361. doi: 10.3389/fpsyt.2020.00361. eCollection 2020.
• Background Enkavi G, Girych M, Moliner R, Vattulainen I, Castren E. TrkB transmembrane domain: bridging structural understanding with therapeutic strategy. Trends Biochem Sci. 2024 May;49(5):445-456. doi: 10.1016/j.tibs.2024.02.001. Epub 2024 Mar 2.
• Background Dahlstrom M, Madjid N, Nordvall G, Halldin MM, Vazquez-Juarez E, Lindskog M, Sandin J, Winblad B, Eriksdotter M, Forsell P. Identification of Novel Positive Allosteric Modulators of Neurotrophin Receptors for the Treatment of Cognitive Dysfunction. Cells. 2021 Jul 23;10(8):1871. doi: 10.3390/cells10081871.
• Background C. Yates, J. L. Kruse, J. B. Price, A. A. B. Robertson, and S. J. Tye, "Modulating Neuroplasticity: Lessons Learned from Antidepressants and Emerging Novel Therapeutics," Curr Treat Options Psychiatry, vol. 8, no. 4, pp. 229-257, Dec. 2021, doi: 10.1007/S40501-021-00249-9.
• Background Wang Y, Liang J, Xu B, Yang J, Wu Z, Cheng L. TrkB/BDNF signaling pathway and its small molecular agonists in CNS injury. Life Sci. 2024 Jan 1;336:122282. doi: 10.1016/j.lfs.2023.122282. Epub 2023 Nov 24.
• Background Gupta AK, Gupta S, Mehan S, Khan Z, Das Gupta G, Narula AS. Exploring the Connection Between BDNF/TrkB and AC/cAMP/PKA/CREB Signaling Pathways: Potential for Neuroprotection and Therapeutic Targets for Neurological Disorders. Mol Neurobiol. 2025 Nov;62(11):14627-14659. doi: 10.1007/s12035-025-05001-5. Epub 2025 May 9.
• Background Didden R, VanDerNagel J, Delforterie M, van Duijvenbode N. Substance use disorders in people with intellectual disability. Curr Opin Psychiatry. 2020 Mar;33(2):124-129. doi: 10.1097/YCO.0000000000000569.
• Background Prosser H, Moss S, Costello H, Simpson N, Patel P, Rowe S. Reliability and validity of the Mini PAS-ADD for assessing psychiatric disorders in adults with intellectual disability. J Intellect Disabil Res. 1998 Aug;42 ( Pt 4):264-72. doi: 10.1046/j.1365-2788.1998.00146.x.
• Background Berry-Kravis EM, Harnett MD, Reines SA, Reese MA, Ethridge LE, Outterson AH, Michalak C, Furman J, Gurney ME. Inhibition of phosphodiesterase-4D in adults with fragile X syndrome: a randomized, placebo-controlled, phase 2 clinical trial. Nat Med. 2021 May;27(5):862-870. doi: 10.1038/s41591-021-01321-w. Epub 2021 Apr 29.
• Background Nelson MA, Schmitt LM, Horn PS, Berry-Kravis E, Hessl D, Shaffer RC, Carpenter R, Budimirovic DB, Wang P, Reisinger DL, Walton-Bowen K, Erickson CA. Parent-Reported Outcome Measures for Individuals with Fragile X Syndrome: Clinically Meaningful Change Thresholds. J Autism Dev Disord. 2026 Apr;56(4):1658-1670. doi: 10.1007/s10803-024-06634-6. Epub 2024 Nov 23.
• Background Crawford H, Moss J, Groves L, Dowlen R, Nelson L, Reid D, Oliver C. A Behavioural Assessment of Social Anxiety and Social Motivation in Fragile X, Cornelia de Lange and Rubinstein-Taybi Syndromes. J Autism Dev Disord. 2020 Jan;50(1):127-144. doi: 10.1007/s10803-019-04232-5.
• Background Cregenzan-Royo O, Brun-Gasca C, Fornieles-Deu A. Behavior Problems and Social Competence in Fragile X Syndrome: A Systematic Review. Genes (Basel). 2022 Jan 30;13(2):280. doi: 10.3390/genes13020280.
• Background Budimirovic DB, Dominick KC, Gabis LV, Adams M, Adera M, Huang L, Ventola P, Tartaglia NR, Berry-Kravis E. Gaboxadol in Fragile X Syndrome: A 12-Week Randomized, Double-Blind, Parallel-Group, Phase 2a Study. Front Pharmacol. 2021 Oct 8;12:757825. doi: 10.3389/fphar.2021.757825. eCollection 2021.
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• Background E. Merikle, V. Patel, T. Sebree, ; Carolyn Kreusser, and H. H. Heussler, "Content Validity in Support of the ABC-C FXS and Subscales in Fragile X Syndrome," J Autism Dev Disord, vol. 113, no. 6, pp. 1377-92, 2008.
• Background Sansone SM, Widaman KF, Hall SS, Reiss AL, Lightbody A, Kaufmann WE, Berry-Kravis E, Lachiewicz A, Brown EC, Hessl D. Psychometric study of the Aberrant Behavior Checklist in Fragile X Syndrome and implications for targeted treatment. J Autism Dev Disord. 2012 Jul;42(7):1377-92. doi: 10.1007/s10803-011-1370-2.
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• Background Shields RH, Kaat AJ, McKenzie FJ, Drayton A, Sansone SM, Coleman J, Michalak C, Riley K, Berry-Kravis E, Gershon RC, Widaman KF, Hessl D. Validation of the NIH Toolbox Cognitive Battery in intellectual disability. Neurology. 2020 Mar 24;94(12):e1229-e1240. doi: 10.1212/WNL.0000000000009131. Epub 2020 Feb 24.
• Background "Enobio® EEG systems | Neuroelectrics." Accessed: Mar. 27, 2024. [Online]. Available: https://www.neuroelectrics.com/solutions/enobio
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• Background Tassone F, Hagerman RJ, Ikle DN, Dyer PN, Lampe M, Willemsen R, Oostra BA, Taylor AK. FMRP expression as a potential prognostic indicator in fragile X syndrome. Am J Med Genet. 1999 May 28;84(3):250-61.
• Background Hagerman RJ, Berry-Kravis E, Kaufmann WE, Ono MY, Tartaglia N, Lachiewicz A, Kronk R, Delahunty C, Hessl D, Visootsak J, Picker J, Gane L, Tranfaglia M. Advances in the treatment of fragile X syndrome. Pediatrics. 2009 Jan;123(1):378-90. doi: 10.1542/peds.2008-0317.
• Background de Vries BB, Wiegers AM, Smits AP, Mohkamsing S, Duivenvoorden HJ, Fryns JP, Curfs LM, Halley DJ, Oostra BA, van den Ouweland AM, Niermeijer MF. Mental status of females with an FMR1 gene full mutation. Am J Hum Genet. 1996 May;58(5):1025-32.
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• Background Erickson CA, Kaufmann WE, Budimirovic DB, Lachiewicz A, Haas-Givler B, Miller RM, Weber JD, Abbeduto L, Hessl D, Hagerman RJ, Berry-Kravis E. Best Practices in Fragile X Syndrome Treatment Development. Brain Sci. 2018 Dec 15;8(12):224. doi: 10.3390/brainsci8120224.
• Background Jacquemont S, Berry-Kravis E, Hagerman R, von Raison F, Gasparini F, Apostol G, Ufer M, Des Portes V, Gomez-Mancilla B. The challenges of clinical trials in fragile X syndrome. Psychopharmacology (Berl). 2014 Mar;231(6):1237-50. doi: 10.1007/s00213-013-3289-0. Epub 2013 Oct 31.
• Background Erickson CA, Davenport MH, Schaefer TL, Wink LK, Pedapati EV, Sweeney JA, Fitzpatrick SE, Brown WT, Budimirovic D, Hagerman RJ, Hessl D, Kaufmann WE, Berry-Kravis E. Fragile X targeted pharmacotherapy: lessons learned and future directions. J Neurodev Disord. 2017 Jun 12;9:7. doi: 10.1186/s11689-017-9186-9. eCollection 2017.
• Background van der Lei MB, Kooy RF. From Discovery to Innovative Translational Approaches in 80 Years of Fragile X Syndrome Research. Biomedicines. 2025 Mar 27;13(4):805. doi: 10.3390/biomedicines13040805.
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Indications